1

Midterm reminder April 13Covers lectures 10-18 (this

includes Professor RoelinkʼsApril 6 lecture)

Office hours this week:Tu & Th 2-4 PM

No office hours Tu, April 7

Garriga midterm review sessionApril 12, 5-7 PM 100 GPB

Genetic diseases and geneticscreening

Reading: pp 200-202, 316

OutlineAutosomal recessive genetic

diseasesScreening

Autosomal recessivemutations

The story of three geneticdiseases

PhenylketonuriaSickle-Cell DiseaseTay-Sachs Disease

Autosomal recessive geneticdiseases

-inheritance patterns-disease phenotype

-prevalence

Phenylketonuria (PKU), Sickle-Cell Diseaseand Tay-Sachs Disease are autosomal

recessive diseases.

Disease is expressed inmatings between carriers(heterozygotes).

Most affected individualshave unaffected parents.

Increased frequency withinbreeding.

carrier

2

Frequencies ofSickle-Cell Anemia and Tay-Sachs

Disease alleles in different populations.

Sickle-Cell Disease10-40% of the population in regions of

equatorial Africa are carriers7-10% of African Americans are carriers

<1% of South Africans are carriers

Tay-Sachs1/25 American Ashkenazi Jews are carriers1/300 in the general population are carriers

Why are the frequencies of somedisease alleles so high?

Explanation #1Heterozygote advantage

Explanation #2Founder effect

Major protein in red bloodcells.

Hemoglobin is made of fourpolypeptide chains--2 alphaand 2 beta chains--and fourheme-iron complexes. Thesecomplexes bind O2.

Hemoglobin releases CO2 and binds O2 when CO2concentrations are low. i.e., in the lungs. Hb bindsCO2 and releases O2 when CO2 concentrationshigh.

Hemoglobin A single amino acid change in the betapeptide results in sickle cell anemia

Results of RBC sicklingBreakdown of RBC

anemiaFatigue, shortness of breath

Jaundice

Blood vessel cloggingOrgan and joint pain

Organ damageStroke

3

All 50 States, DC, Puerto Rico and theVirgin Islands do a simple blood test for

HbS in newborns.

Treatment is effective, and whendiagnosed early, sickle cell patients can

live beyond 40 years.

Why is the carrier frequency so high?

Carriers have an advantagein malaria-infested areas

Genotype disease malariaHbB/HbB normal susceptibleHbS/HbB normal resistant

Tay Sachs

Progressive disease with an onset in infancy ofdevelopmental retardation, followed by paralysis,dementia and blindness. Death occurs in the second orthird year of life.

Tay-Sachs disease is caused by mutation in thehexosaminidase A gene, which removes fattysubstances called gangliosides. When hemosaminidaseA is lacking, gangliosides build up in neurons.

The Founder Effect

4

OutlineAutosomal recessive genetic

diseasesScreening-Newborn-Prenatal

If left untreated PKU can causesevere mental retardation.

Mutations in the gene encoding phenylalaninehydroxylase cause PKU. 1/14,000 births

Phenylalanine(essential amino acid that we get in our diet).

phenylalanine hydroxylase

Tyrosine

Mental retardation from PKU has beeneliminated in the U.S.

All newborns are tested for PKU using a simple blood testthat measures phenylalanine.

Infants with PKU are placed on a phenylalanine restricteddiet. Later in life, after neural development is largelycompleted, PKUindividuals can resumea normal diet.

PKU is described in yourtextbook on pp248-252.

States decide what genetic diseasesare screened in newborns

Tandem Mass Spectrometry has thepotential to test for many metabolites in

newborns

Newborn screeningInfants in all 50 states tested for PKU, sicklecell disease, congenital adrenal hyperplasia

and a many others

5

What about prenatal testing?

UltrasoundChorionic villus sampling (CVS)

Amniocentesis

Amniocentesis

Amniocentesis

Aneuploidykaryotype

Open neural tube defectsAlpha-fetoprotein & acetylcholinesterase

Genetic diseasesPCR

Tay Sachs Disease Testing

Carriers can be identified by a simple bloodtest that measures hexosaminidase Aactivity.

In the 1970s, the families of affected childrenbegan a program that focused on educationof Jewish groups to the risk of Tay Sachs.The community was also instructed on howto seek genetic testing and counseling. Tay-Sachs disease is almost never encounteredtoday in Ashkenazi Jews.

As the genes for more geneticdiseases are identified, molecular

genetic approaches can be also beused to screen for many genetic

diseases. In principle, 100s ofgenetic traits could be screened.

How many diseases?

Who should pay?

Who should get the information?